Copy number gain of pro-inflammatory genes in patients with HBV-related acute-on-chronic liver failure
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RESEARCH ARTICLE
Copy number gain of pro‑inflammatory genes in patients with HBV‑related acute‑on‑chronic liver failure Fengming Sun1,2†, Wenting Tan1,2†, Yunjie Dan1,2, Xiuhua Wang1,2, Yanzhi Guo1,2 and Guohong Deng1,2*
Abstract Background: Host genetic factors such as single nucleotide variations may play a crucial role in the onset and progression of HBV-related acute-on-chronic liver failure (ACLF). However, the underlying genomic copy number variations (CNVs) involved in the pathology are currently unclear. Methods: We genotyped two cohorts with 389 HBV-related ACLF patients and 391 asymptomatic HBV carriers (AsCs), and then carried out CNV-based global burden analysis and a genome-wide association study (GWAS). Results: For 1874 rare CNVs, HBV-related ACLF patients exhibited a high burden of deletion segments with a size of 100–200 kb (P value = 0.04), and the related genes were significantly enriched in leukocyte transendothelial migration pathway (P value = 4.68 × 10–3). For 352 common CNVs, GWAS predicted 17 significant association signals, and the peak one was a duplication segment located on 1p36.13 (~ 38 Kb, P value = 1.99 × 10–4, OR = 2.66). The associated CNVs resulted in more copy number of pro-inflammatory genes (MST1L, DEFB, and HCG4B) in HBV-related ACLF patients than in AsC controls. Conclusions: Our results suggested that the impact of host CNV on HBV-related ACLF may be through decreasing natural immunity and enhancing host inflammatory response during HBV infection. The findings highlighted the potential importance of gene dosage on excessive hepatic inflammation of this disease. Keywords: Copy number variations, HBV-related ACLF, GWAS, HBV-ACLF, Acute-on-chronic liver failure Background Hepatitis B Virus (HBV) infection is regarded as a global health issue. The global chronic HBV infection rate in 2015 was estimated at 3.5% involving 257 million people, of which 15–25% died of HBV-related cirrhosis or liver cancer [1]. Caused by severe acute exacerbation of chronic hepatitis B (CHB), HBV-related acute-onchronic liver failure (ACLF) is a severe life-threatening *Correspondence: [email protected] † Fengming Sun and Wenting Tan have contributed equally to this study 1 Department of Infectious Diseases, Southwest Hospital, Third Military Medical University (Army Medical University), Shapingba District, Chongqing 400038, China Full list of author information is available at the end of the article
disease that exhibits a high 28-day mortality rate of more than 15% [2]. Several risk factors have been suggested to be involved in this common complex disease, including hereditary factors, host characteristics, viral factors, and vigorous immune responses [3–5]. However, the pathological processes are still poorly understood. Host genetic factors likely play a crucial role in the pathogenesis of HBV-related ACLF. Our group has recently performed a SNP-based genome-wide association study (GWAS) of this disease, and identified a highly associated variant rs3129859*C [6]. The related
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